Themis是一个对T细胞发育至关重要的分子，以往的研究发现Themis会与接头分子GRB2及磷酸酶SHP1结合成一个复合体来负调节TCR信号的传导。我们的前期研究发现Themis只在一定的信号强度内发挥调节作用，同时不影响经过激动肽选择的Treg细胞的胸腺发育，表明Themis可能参与TCR信号阈值的设定。在分子水平上，我们发现Themis的酪氨酸磷酸化程度在不同信号强度刺激下有明显差异，提示Themis在TCR信号传导中可能起到“刹车”的作用，即只在一定信号强度范围内衰减TCR接受到的来自自身肽-MHC复合体的信号，并参与TCR信号阈值的设定，这个阈值似乎位于阳性选择和“激动肽选择”之间。在Themis缺失的情况下，由于TCR信号不能被正常衰减而导致整个信号阈值发生了改变，胸腺T细胞因此错误地越过阳性选择而直接地进入阴性选择。本课题将在分子，细胞，及动物水平上系统地研究和验证这一假说。

Themis plays an important role in T cell development. Previous studies showed that Themis can bind adaptor protein GRB2 and phosphatase SHP1,forming a Themis-GRB2-SHP1 complex and dampenig TCR singaling. Our preliminary data found that Themis can only exert its function within a range of TCR signal strength, and that Themis-deficiency doesn’t impair agonist-selected Tregs.These results suggested that Themis may be involved in setting the signal threshold of TCR during T cell development. Furthermore, at the molecular level, we found that the phosphorylation status of Themis is differentially regulated upon different TCR stimulating strength. All these results point to a hypothesis that Themis may function as a “brake”, that it can only attenuate the TCR singal strength within a range and help setting the threshold between positive selection and agonist selection. Thus without Themis, TCR signal can not be properly attenuated, and developing thymocytes will mistakely “jump into” negative selection when they should be positively selected. In this project we will test this hypothesis at molecular, cellular, and animal level.